12-11393191-C-A

Position:

• chr12-11393191-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006248.4(PRB2):​c.887G>T​(p.Ser296Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 16)
• Consequence: PRB2 NM_006248.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

PRB2 (HGNC:9338): (proline rich protein BstNI subfamily 2) This gene encodes a member of the heterogeneous family of basic, proline-rich, human salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature isoforms before secretion from the parotid glands. Multiple alleles of this gene exhibiting variations in the length of the tandem repeats, polymorphic cleavage sites and polymorphic stop codons have been identified. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. [provided by RefSeq, May 2023]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10706553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRB2	NM_006248.4	c.887G>T	p.Ser296Ile	missense_variant	3/4	ENST00000389362.6	NP_006239.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRB2	ENST00000389362.6	c.887G>T	p.Ser296Ile	missense_variant	3/4	5	NM_006248.4	ENSP00000374013	P1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 16

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.887G>T (p.S296I) alteration is located in exon 3 (coding exon 3) of the PRB2 gene. This alteration results from a G to T substitution at nucleotide position 887, causing the serine (S) at amino acid position 296 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.3
DANN	Benign	0.80
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0040	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.079
Sift4G	Benign	0.29	T
Vest4		0.13
MutPred		0.47		Loss of phosphorylation at S296 (P = 4e-04);
MVP		0.12
MPC		0.077
ClinPred		0.11	T
GERP RS		-2.7
gMVP		0.097

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752509304; hg19: chr12-11546125;